Studies of constitutional bone marrow failure have centered on Fanconi anemia (FA), as several genes responsible for this inherited syndrome have been identified. For the A and C subgroups, which account for the majority of cases in the USA and Europe, the respective gene products, FAA and FAC, have been cloned but their function has not yet been determined. Using the yeast two-hybrid system, we have identified several proteins that interact with either FAC or FAA. GRP94, a molecular chaperone, has been shown to interact with FAC and to regulate its intracellular expression. In other experiments, we have also found that one of the functions of normal FAC is in the regulation of apoptosis. For example, FAC suppresses cell death induced by the Fas death receptor in a transgenic mouse model. In a unique clinical trial, we have developed a gene transfer protocol for FA-C patients. The normal FAC gene has been introduced into human patients' blood cells and reinfused in an effort to correct the underlying bone marrow failure. The protocol has been demonstrated to be safe, and FAC has been detected in a population of multi- potent progenitor cells. Although blood counts have not been consistently improved, progenitor cells, including cells now resistant to a drug against which FA cells are unusually sensitive, have increased in several treated patients after multiple cycles of gene transfer.